HIV infection strongly correlates with chronic immune activation leading to an acquired immune-deficient state progression. Despite effective highly active antiretroviral therapy (HAART), chronic infection persists at higher levels, yet the stimuli inducing inflammation and the mechanisms for its persistence remain incompletely understood. Current concept supports an important role for bacterial translocation and persistent endotoxin- mediated TLR4 stimulation resulting in chronic immune activation state. However, preliminary data for the current application challenges this concept, and suggests that TLR8 stimulation by HIV-derived ssRNA may represent the predominant mechanism contributing to chronic immune activation. Our preliminary data demonstrate the detection of novel HIV-derived microRNAs (vmiRs) in serum from HIV+ persons. Furthermore, HIV+ human macrophages package these novel vmiRs in exosomes that are released into culture supernatants. They promote macrophage TNF? release from bystander cells in a TLR8-dependent manner. Importantly, HIV vmiR-mediated release of proinflammatory cytokines is more potent than endotoxin (LPS). Finally, HIV vmiR-mediated proinflammatory cytokines can be blocked by our exogenous antagomirs. Collectively, these preliminary data support the central hypothesis that HIV-derived vmiR release by macrophages induces chronic immune activation through TLR8-mediated inflammatory signaling contributing to AIDS pathogenesis. The research proposal will accomplish three specific aims: 1) To test the hypothesis that HIV-derived vmiRs are released by activated macrophages via an exosomal pathway and promote an inflammatory phenotype in bystander macrophages. 2) To test the hypothesis that specific HIV-derived vmiRs promote macrophage proinflammatory cytokine release through endosomal TLR8 recognition and signaling. 3) To test the hypothesis that HIV-derived vmiR induction of proinflammatory cytokine release is inhibited by specific antagomirs targeting HIV-derived vmiRs. The research project is novel because it presents the discovery of novel HIV-derived vmiRs encapsulated in exosomes are released into the circulation. They confer an inflammatory phenotype on target cells. Furthermore, this discovery challenges the current paradigm underlying how HIV infection induces chronic immune activation. This novel concept has therapeutic potential since it could lead to nucleic acid-based therapeutics and a novel exosome-encapsulated antagomir delivery system.